MOLECULES
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2024
·Vol. 29
·期 11
·2436
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IF 4.2
Changlin Xu,Nida Amna,Yuchen Shi,Rong Sun,Chenhui Weng,Jiaoyu Chen,Huaxing Dai,Chao Wang
Myeloid-derived suppressor cells (MDSCs) are recognized as major immune suppressor cells in the tumor microenvironment that may inhibit immune checkpoint blockade (ICB) therapy. Here, we developed a Stattic-loaded mesoporous silica nanoparticle (PEG-MSN-Stattic) delivery system to tumor sites to reduce the number of MDSCs in tumors. This approach is able to significantly deplete intratumoral MSDCs and thereby increase the infiltration of T lymphocytes in tumors to enhance ICB therapy. Our approach may provide a drug delivery strategy for regulating the tumor microenvironment and enhancing cancer immunotherapy efficacy.
研究领域:
肿瘤学
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免疫学
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纳米医学
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DOI
PubMed
高影响因子
HEPATOLOGY
·
2024
·
IF 12.9
Zhang Sitong,Sun Zhongquan,Chen Zhenhua,Bi Yanli,Wei Shenyu,Mao Zhengwei,Jin Jin,Ding Yuan,Wang Weilin
Background & Aims: Liver ischemia-reperfusion injury (IRI) is a common complication of liver transplantation and hepatectomy, and causes acute liver dysfunction and even organ failure. Myeloid-derived suppressor cells (MDSCs) accumulate and play immunosuppressive function in cancers and inflammation. However, the role of MDSCs in liver IRI has not been defined. Approach & Results: We enrolled recipients receiving orthotopic liver transplantation (OLT) and obtained the pre-OLT/post-OLT blood and liver samples. The proportions of MDSCs were significantly elevated after OLT and negatively associated with liver damage. In single-cell RNA-sequencing analysis of liver samples during OLT, two cell clusters with MDSC-like phenotypes were identified and showed maturation and infiltration in post-OLT livers. In mice model, liver IRI mobilized MDSCs and promoted their infiltration in damaged liver, and intrahepatic MDSCs possessed with enhanced immunosuppressive function by up-regulation of STAT3 signaling. Under treatment with αGr-1 antibody or adoptive transfer MDSCs to change the proportion of MDSCs in vivo , we found that intrahepatic MDSCs alleviated liver IRI-induced inflammation and damage by inhibiting M1 macrophage polarization. Mechanistically, bulk RNA-sequencing analysis and in vivo experiments verified that CXCL17 was upregulated by YAP/TEAD1 signaling and subsequently recruited MDSCs via binding with GPR35 during liver IRI. Moreover, hepatic endothelial cells were the major cells responsible for CXCL17 expression in injured livers, among which hypoxia-reoxygenation stimulation activated YAP/TEAD1 complex to promote CXCL17 transcription. Conclusions: Endothelial YAP/TEAD1-CXCL17 signaling recruited MDSCs to attenuate liver IRI, providing evidence of a therapeutic potential for managing IRI in liver surgery. Export
研究领域:
医学
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免疫学
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肝脏病学
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PubMed
高影响因子
Frontiers in Pharmacology
·
2021
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IF 5.811
Botao Wang,Lei Yang,Tianyu Liu,Jing Xun,Yuzhen Zhuo,Lanqiu Zhang,Qi Zhang,Ximo Wang
The poor immunotherapy of pancreatic cancer is mainly due to its complex immunosuppressive microenvironment. The Mediterranean diet contributes to low cancer incidence. Hydroxytyrosol (HT) derived from olive oil has multiple health-promoting effects, but its therapeutic effect on pancreatic cancer remains controversial. Here, we evaluated the inhibitory effect of HT on mouse pancreatic cancer, and the effect of HT on the immune microenvironment. We found that HT can inhibit the proliferation of Panc 02 cells through signal transducer and activator of transcription (STAT) 3/Cyclin D1 signaling pathway. In the tumor-bearing mice treated with HT, the orthotopic pancreatic tumors were suppressed, accompanied by a decrease in the proportion of myeloid-derived suppressor cells (MDSCs) and an increase in the proportion of M1 macrophages. In addition, we found that HT inhibited the expression of immunosuppressive molecules in bone marrow (BM)-derived MDSCs, as well as down-regulated CCAAT/enhancer-binding protein beta (C/EBPβ) and phosphorylation of STAT3. Moreover, HT enhanced the anti-tumor effect of anti-CD47 antibody in vivo . HT combined with plumbagin (PLB) induced more Panc 02 cells death than HT or PLB alone. This combination therapy not only inhibited the accumulation of MDSCs, but also promoted the infiltration of CD4 + and CD8 + T cells in the tumors. In summary, HT is a potential immunomodulatory drug for the treatment of pancreatic cancer.
研究领域:
肿瘤学
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免疫学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF PHARMACEUTICS
·
2020
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IF 4.845
Min Jiang,Kaiyong He,Tong Qiu,Jiahui Sun,Qi Liu,Xueqiong Zhang,Hua Zheng
We induced changes in the tumor microenvironment (TME) through the synergistic actions of two drugs used in breast cancer therapy. The anti-fibrotic drug silibinin (SLB) targets tumor-associated fibroblasts and exerts immune-mediated anti-cancer effects. IPI-549, an efficient and highly selective phosphoinositide-3-kinase-gamma (PI3Kγ) inhibitor, was applied to alter the balance of immunosuppressive cells by inhibiting PI3Kγ molecules; it also promotes anti-tumor immunity. We developed nanoparticle formulations to encapsulate both drugs into the targeting carrier aminoethyl anisamide-polyethylene glycol-polycaprolactone (AEAA-PEG-PCL) respectively. The drugs were intravenously delivered in mice and resulted in an increase in anti-tumor efficacy and apoptotic tumor tissue compared with either IPI-549 or SLB alone in 4T1 breast cancer cell-derived tumors. Furthermore, a significant reduction in regulatory T (Treg) cells and myeloid suppressor cells (MDSCs) was observed. A normalized TME structure was also observed, including angiogenesis suppression, antifibrotic effects and the inhibition of collagen formation in the tumor tissue, significantly enhancing the anti-tumor effects. In summary, this combination strategy may offer an alternative treatment for breast cancer.
研究领域:
肿瘤学
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药理学
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免疫学
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纳米医学
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DOI
PubMed
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-16
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IF 10.6
Lan Zhou,Liu Wei-Jia,Yin Wu-Wei,Yang Sheng-Ren,Cui Hao,Zou Ke-Long,Cheng Guo-Wang,Chen Hao,Han Yan-Hua,Rao Lang,Tian Rui,Li Ling-Ling,Zhao Yu-Yue,Yu Guang-Tao
Photothermal therapy is favored by cancer researchers due to its advantages such as controllable initiation, direct killing and immune promotion. However, the low enrichment efficiency of photosensitizer in tumor site and the limited effect of single use limits the further development of photothermal therapy. Herein, a photo-responsive multifunctional nanosystem was designed for cancer therapy, in which myeloid-derived suppressor cell (MDSC) membrane vesicle encapsulated decitabine-loaded black phosphorous (BP) nanosheets (BP@ Decitabine @MDSCs, named BDM). The BDM demonstrated excellent biosafety and biochemical characteristics, providing a suitable microenvironment for cancer cell killing. First, the BDM achieves the ability to be highly enriched at tumor sites by inheriting the ability of MDSCs to actively target tumor microenvironment. And then, BP nanosheets achieves hyperthermia and induces mitochondrial damage by its photothermal and photodynamic properties, which enhancing anti-tumor immunity mediated by immunogenic cell death (ICD). Meanwhile, intra-tumoral release of decitabine induced G2/M cell cycle arrest, further promoting tumor cell apoptosis. In vivo, the BMD showed significant inhibition of tumor growth with down-regulation of PCNA expression and increased expression of high mobility group B1 (HMGB1), calreticulin (CRT) and caspase 3. Flow cytometry revealed significantly decreased infiltration of MDSCs and M2-macrophages along with an increased proportion of CD4+, CD8+ T cells as well as CD103+ DCs, suggesting a potentiated anti-tumor immune response. In summary, BDM realizes photothermal therapy/photodynamic therapy synergized chemotherapy for cancer.
研究领域:
癌症研究
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纳米技术
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免疫治疗
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药学
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DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
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2026
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IF 12.5
Wuguang Chang,Duo Xu,Wenxiang Ding,Meilin Yang,Yan Tan,Henry H.Y. Tong,Qiu Huang,Dan Li
[ 18 F]FETQA‑PET visualizes MDSCs‑driven pre‑metastatic niches non‑invasively. • Preoperative lung uptake of [ 18 F]FETQA predicts postoperative metastasis. • [ 18 F]FETQA‑PET‑based risk stratification guides adjuvant therapy selection. • [ 18 F]FETQA‑PET enables monitoring of therapy response targeting pre‑metastatic niches. Postoperative metastasis persists as a predominant cause of mortality in solid tumors, largely driven by the establishment of the immunosuppressive pre-metastatic niche. The development of effective interventional strategies is currently hindered by the inability to detect the pre-metastatic niche within anatomically normal tissues. To address this limitation, we focused on myeloid-derived suppressor cells (MDSCs) as key mediators of the pre-metastatic niche and developed [ 18 F]FETQA, a novel positron emission tomography (PET) tracer targeting S100A9, a key marker of MDSCs. In spontaneous tumor metastasis models, [ 18 F]FETQA-PET allowed non-invasive visualization of the lung pre-metastatic niche, with tracer uptake demonstrating a strong positive correlation with local MDSCs burden. Preoperative quantification of [ 18 F]FETQA lung uptake serves as a significant predictor for postoperative lung metastasis development. Moreover, the integration of radiomic features with [ 18 F]FETQA lung uptake enables the construction of an enhanced predictive model (area under curve = 0.98) for stratifying postoperative metastasis risk. Finally, preoperative risk stratification utilizing [ 18 F]FETQA-PET imaging effectively identifies individuals at high-risk for metastasis and informs risk-stratified intervention, thereby alleviating the burden of the pre-metastatic niche and attenuating metastatic progression. This study establishes [ 18 F]FETQA-PET as a novel molecular imaging tool that enables non-invasive visualization of the MDSCs-driven pre-metastatic niche, functions as a predictor for postoperative lung metastasis development, and facilitates image-guided risk stratification to provide a basis for therapeutic decision making, thereby offering an integrated strategy to intercept metastatic progression. Download: Download high-res image (280KB) Download: Download full-size image
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DOI
高影响因子
Theranostics
·
2026
·Vol. 16
·期 5
·2372
·
IF 13.3
Jiawen Chen,Junfeng Liu,Xiaoting Zhang,Xi Li,Jinming Fan,Shengchao Zhao,Junbin Liu,Bin Zhou,Ke Zhang
Background: Hepatocellular carcinoma (HCC), the major form of primary liver cancer, contributes markedly to cancer-related mortality worldwide and remains a serious global health concern, particularly affecting individuals with underlying chronic liver disorders. In hepatocellular carcinoma, insufficient radiofrequency ablation (iRFA) has been reported to drive local tumor relapse and distant spread, possibly by aggravating the immunosuppressive features of the tumor microenvironment. The present work seeks to clarify the underlying pathways driving the development of an immunosuppressive milieu after RFA and to identify potential therapeutic approaches to counteract this process. Methods: An injectable hydrogel composed of quaternized chitosan (QCS) and tannic acid (TA) was constructed to encapsulate verteporfin (VP), a well-established photosensitizer that has been clinically applied for treating neovascular retinal disorders such as age-related macular disease. Beyond its ophthalmologic application, VP has recently been reported to display anti-tumor activity through inhibition of oncogenic regulators such as Yes-associated protein (YAP), indicating its potential utility in cancer therapy. This hydrogel formulation is designed to target residual tumor tissue post-RFA, providing localized delivery and sustained release of VP to enhance anti-tumor immune responses. Results: Our findings identified YAP activation as a critical mediator of immunosuppression in residual tumors following RFA. Pharmacological inhibition of YAP significantly reduced the infiltration of myeloid-derived suppressor cells (MDSCs) and effectively reversed the immunosuppressive microenvironment conditions. Furthermore, the QCS/TA hydrogel enabled sustained local release of VP, resulting in enhanced antitumor immune responses via MDSC suppression. When administered as an adjuvant therapy following suboptimal RFA, the hydrogel markedly inhibited the progression of residual tumors, highlighting its therapeutic potential in improving post-RFA outcomes. Conclusion: Collectively, our data suggest YAP pathway inhibition as a promising immunomodulatory strategy to complement RFA in HCC management. This work demonstrates that the QCS/TA hydrogel-based delivery system can remodel the tumor immune milieu to overcome immunosuppression and delay post-ablation tumor recurrence, supporting its potential as a translational drug delivery strategy.
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PubMed
高影响因子
Journal of Translational Medicine
·
2025
·Vol. 23
·期 1
·1-19
·
IF 7.5
Hu Songliu,Zhan Ning,Li Jian,Wang Liqun,Liu Yiyan,Jin Ke,Wang Yixuan,Zhang Juxuan,Chen Yiyang,Bai Yang,Wang Yichong,Qi Lishuang,Liu Shilong
Background Radiotherapy is commonly used for locoregionally advanced NSCLC, but radioresistance is a clinical challenge. The long non-coding RNA CBR3-AS1 mediates radioresistance in NSCLC, yet the underlying molecular mechanism is unclear. This study aims to explore whether and how N6-methyladenosine (m6A) modification regulates CBR3-AS1 expression and promotes NSCLC radioresistance. Methods Integrative bioinformatics analyses were used to investigate the m6A methyltransferases that were associated with CBR3-AS1 expression and radioresistance of patients using data from The Cancer Genome Atlas of lung adenocarcinoma and squamous cell carcinoma. Clinical samples of 133 patients with NSCLC was collected to validate the correlation of the methyltransferase with radioresistance. The functional role and molecular mechanism of the methyltransferase in radioresistance was investigated through a series of in vitro experiments including m6A MeRIP-PCR, lentivirus transfection, RNA immunoprecipitation, Luciferase reporter, Colony formation, Transwell invasion, Flow cytometry, ELISA and TUNEL assay and in vivo experiments. Results The methyltransferase RNA binding motif protein 15 (RBM15) was identified as it was significantly positively correlated with CBR3-AS1 expression and overall survival of NSCLC patients receiving radiotherapy. The clinical samples demonstrated that the high protein expression of RBM15 was significantly enriched in patients with radioresistance as well as associated with poor prognosis of patients receiving radiotherapy. In vitro, RBM15 silencing enhanced the effects of radiation on the growth and invasion inhibition, and apoptosis induction of NSCLC cells; RBM15 overexpression had the opposite effects. Mechanistically, RBM15 induced CBR3-AS1 upregulation via an m6A-IGF2BP3-dependent mechanism, inducing CXCL1 expression by sponging miR-409-3p to recruit myeloid-derived suppressor cells (MDSCs) and inhibit T cell activity. In vivo, RBM15 silencing suppressed MDSC invasiveness and enhanced CD8 + and CD4 + T cell infiltration, causing NSCLC cells to overcome radioresistance. Conclusion Our study identifies methyltransferase RBM15 as a potential therapeutic target for NSCLC radioresistance whose inhibition reverses resistance through limiting MDSC recruitment via the m6A-IGF2BP3-CBR3-AS1/miR-409-3p/CXCL1 axis. Graphical
研究领域:
肿瘤学
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分子生物学
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表观遗传学
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DOI
PubMed
高影响因子
JOURNAL OF INTERFERON AND CYTOKINE RESEARCH
·
2025
·
IF 1.8
Jiaojiao Ren,Jun Ying,Haijian Liu,Shanshan Hu,Jiangdong Li,Danfei Zhou
Background: This study was designed to explore the action mechanism of stimulator of interferon genes (STING) on the differentiation of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment of lung cancer.Methods: Bioinformatics analysis yielded a potential pathway for STING to regulate MDSC differentiation, the interferon regulatory factor 3 (IRF3)/NF-κB axis. The transfection efficiency of STING overexpression plasmid and small interfering RNA against IRF3 (siIRF3) was examined by quantitative real-time polymerase chain reaction (qRT-PCR). After transfection, A9 cells were co-cultured with extracted bone marrow cells (BMCs). MDSC differentiation, protein expression of the IRF3/NF-κB pathway, and changes in nuclear translocation of NF-κB were analyzed by flow cytometry, Western blot, and immunofluorescence staining experiments. A transplanted tumor mouse model was used for in vivo experiments. After cyclic diadenyl monophosphate (CDA; STING agonist) treatment, changes in MDSC differentiation and protein expression of the IRF3/NF-κB axis in transplanted tumors were verified by immunohistochemical staining, qRT-PCR, and Western blot.Results: Coculture of A9 cells and BMCs promoted MDSC differentiation, inhibited activation of IRF3/NF-κB signal in A9 cells, and boosted nuclear translocation of NF-κB. However, after the upregulation of STING, IRF3/NF-κB signal was activated, while MDSC differentiation and nuclear translocation of NF-κB were inhibited. SiIRF3 reversed the effects of STING overexpression. In vivo, CDA dampened MDSC differentiation and promoted protein expression of the IRF3/NF-κB axis.Conclusion: STING signal in lung cancer cells inhibits MDSC differentiation through activation of the IRF3/NF-κB pathway.
研究领域:
肿瘤学
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免疫学
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分子生物学
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DOI
PubMed
高影响因子
ADVANCED MATERIALS
·
2024
·
IF 27.4
Mei Long,Yanfeng Zhou,Daoxia Guo,Qingyun Zhu,Huan Liang,Xiaoyuan Ji,Nan Chen,Haiyun Song
Epigenetic drugs (epi-drugs) can destruct cancer cells and initiate both innate and adaptive immunity, yet they have achieved very limited success in solid tumors so far, partly attributing to their concurrent induction of the myeloid-derived suppressor cell (MDSC) population. Here, dissociable Siamese nanoparticles (SIANPs) are developed for tumor cell-targeted delivery of epi-drug CM-272 and MDSC-targeted delivery of small molecule inhibitor Ibrutinib. The SIANPs are assembled via interparticle DNA annealing and detached via tumor microenvironment-triggered strand separation. Such binary regulation induces endogenous retrovirus expression and immunogenic cell death in tumor cells while restraining the immunosuppressive effects of MDSCs, and synergistically promotes dendritic cell maturation and CD8 + T cell activation for tumor inhibition. Significantly, immune microenvironment remodeling via SIANPs further overcomes tumor resistance to immune checkpoint blockade therapy. This study represents a two-pronged approach for orchestrating immune responses, and paves a new way for employing epi-drugs in cancer immunotherapy.
研究领域:
癌症免疫疗法
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纳米技术
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药理学
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免疫学
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2023
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IF 10
Wenjing Mo,Shujie Liu,Xiaozhi Zhao,Fayun Wei,Yuhang Li,Xinan Sheng,Wenmin Cao,Meng Ding,Wenlong Zhang,Xiaoqing Chen,Longxiyu Meng,Sheng Yao,Wenli Diao,Hui Wei,Hongqian Guo
Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), two immunosuppressive myeloid components within the tumor microenvironment (TME), represent fundamental barriers in cancer immunotherapy, whereas current nanomedicines rarely exert dual modulatory roles on these cell types simultaneously. Reactive oxygen species (ROS) not only mediates MDSC-induced immunosuppression but also triggers differentiation and polarization of M2-TAMs. Herein, an ROS scavenging nanozyme, Zr-CeO, with enhanced superoxide dismutase- and catalase-like activities for renal tumor growth inhibition is reported. Mechanistically, intracellular ROS scavenging by Zr-CeO significantly attenuates MDSC immunosuppression via dampening the unfolded protein response, hinders M2-TAM polarization through the ERK and STAT3 pathways, but barely affects neoplastic cells and cancer-associated fibroblasts. Furthermore, Zr-CeO enhances the antitumor effect of PD-1 inhibition in murine renal and breast tumor models, accompanied with substantially decreased MDSC recruitment and reprogrammed phenotype of TAMs in the tumor mass. Upon cell isolation, reversed immunosuppressive phenotypes of MDSCs and TAMs are identified. In addition, Zr-CeO alone or combination therapy enhances T lymphocyte infiltration and IFN- γ production within the TME. Collectively, a promising strategy to impair the quantity and function of immunosuppressive myeloid cells and sensitize immunotherapy in both renal and breast cancers is provided.
研究领域:
癌症免疫治疗
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纳米医学
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免疫学
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肿瘤微环境
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
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2023
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IF 10
Wenhe Luo,Yanqiao Zeng,Qingle Song,Yu Wang,Feng Yuan,Qi Li,Yingnan Liu,Su Li,Nahar Jannatun,Guofang Zhang,Yang Li
Despite the success of immuno-oncology in clinical settings, the therapeutic efficacy is lower than the expectation due to the immunosuppressive inflammatory tumor microenvironment (TME) and the lack of functional lymphocytes caused by exhaustion. To enhance the efficacy of immuno-oncotherapy, a synergistic strategy should be used that can effectively improve the inflammatory TME and increase the tumor infiltration of cytotoxic T lymphocytes (CTLs). Herein, a TME hypoxia-responsive nanogel (NG) is developed to enhance the delivery and penetration of diacerein and (-)-epigallocatechin gallate (EGCG) in tumors. After systemic administration, diacerein effectively improves the tumor immunosuppressive condition through a reduction of MDSCs and Tregs in TME, and induces tumor cell apoptosis via the inhibition of IL-6/STAT3 signal pathway, realizing a strong antitumor effect. Additionally, EGCG can effectively inhibit the expression of PD-L1, restoring the tumor-killing function of CTLs. The infiltration of CTLs increases at the tumor site with activation of systemic immunity after the combination of TIM3 blockade therapy, ultimately resulting in a strong antitumor immune response. This study provides valuable insights for future research on eliciting effective antitumor immunity by suppressing adverse tumor inflammation. The feasible strategy proposed in this work may solve the urgent clinical concerns of the dissatisfactory checkpoint-based immuno-oncotherapy.
研究领域:
肿瘤学
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免疫学
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纳米技术
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药理学
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产品关联
DOI
PubMed
高影响因子
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